Previously, we identified a loss of stromal Cav-1 as a predictive biomarker of early tumor recurrence, metastasis, tamoxifen-resistance, and decreased survival in human breast cancer patients1,2. The predictive value of a loss of stromal Cav-1 was independent of epithelial marker status, as a loss of stromal Cav-1 was predictive in ER+, PR+, HER2+, and triple-negative breast cancer patients1,2. Similarly, in DCIS-patients, a loss of stromal Cav-1 in breast cancers has now been independently validated by six other groups world-wide (Australia, Argentina, Korea, Japan, Egypt, and Leeds-UK)4-8, and has been extended to other types of human cancers, such as advanced prostate cancer9, and metastic melanoma10.
To mechanistically understand the prognostic basis of a loss of stromal Cav-1, we studied Cav-1-deficient-mice. Metabolomic, proteomic, and genomic profiling established that fibroblasts and the mammary fad pads from Cav-1-deficient mice are highly-catabolic, and show strong metabolic-shifts towards autophagy/mitophagy, and aerobic glycolysis, due to increased oxidative stress11-15. Virtually identical catabolic processes and associations with aerobic glycolysis were identified via analysis of laser-captured tumor stroma from human breast cancer patients lacking stromal Cav-116. This led to the proposal of a novel two-compartment model of tumor metabolism, termed the “Reverse Warburg Effect”11, 17-24. In this model, the glycolytic tumor stroma transfers energy-rich nutrients (such as, L-lactate and ketone bodies) to anabolic tumor cells, which then “fuels” mitochondrial metabolism in epithelial cancer cells18.
Thus, we searched for new biomarker(s) of clinical outcome, by analyzing breast cancer cells co-cultured with human fibroblasts. In this co-culture system, Cav-1 is degraded by oxidative-stress-induced autophagy in cancer-associated fibroblasts, resulting in a loss of stromal Cav-1 expression25-28, mirroring what we observe in high-risk breast cancer patients. Under the same conditions, we demonstrated that breast cancer cells induce MCT4 over-expression in stromal fibroblasts, and that MCT4-induction can be prevented by anti-oxidants29. Importantly, MCT4 is the major transporter directly responsible for L-lactate efflux/export from glycolytic cells. As such, MCT4 is a functional biological marker of oxidative stress (pseudo-hypoxia) and aerobic glycolysis in the tumor stroma29.
However, it remains unknown if MCT4 levels are controlled by Cav-1 and/or if stromal MCT4 has any prognostic value as a biomarker in breast cancer patients. To address this issue, we evaluated the prognostic value of stromal Cav-1 and stromal MCT4, in parallel, in the same triple-negative breast cancer patient cohort.
Here, we show that stromal MCT4 (i) is a new biomarker that independently predicts poor overall survival in triple negative (TN) breast cancer patients, and (ii) stromal MCT4 can be used in conjunction with stromal Cav-1, to further stratify the intermediate-risk group into high-risk and low-risk patients.
As MCT4 is a new druggable-target, we suggest that MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers.